Osteoarthritis is a degenerative disease of the articular cartilage, a tissue that covers the surface of all articulating joints in the human body. It is estimated that 20.7 million adults in the US have the disease. The disease is associated with severe pain and limited movement of the affected joints. In the adult, articular cartilage was thought to be a non-renewing cell population. Recently however, it has been suggested that superficial cells of the articular cartilage, which uniquely express the secreted protein lubricin, may provide a source for articular cartilage progenitors during development and possibly in the adult. Articular cartilage consists of superficial, intermediate and deep zone chondrocytes, which display different patterns of gene expression. What is the relationship between these differing chondrocyte zones? Do superficial zone articular chondrocytes give rise to deeper zone cells? What signals are necessary to maintain proliferation, viability and lubricin expression specifically in superficial zone chondrocytes? In this proposal, I outline experiments to examine whether superficial zone chondrocytes give rise to progeny cells restricted to the superficial zone and/or give rise to progeny cells in deeper layers of articular cartilage. In addition, I propose to determine whether muscular movement and exercise, which has been noted to increase the thickness of articular cartilage augments the proliferation of either superficial zone articular cartilage cells or their progeny. Lastly, I propose to determine the role of both Notch and Wnt signaling in maintaining either the proliferation, viability and/or differentiated phenotype of superficial zone chondrocytes. It is my hope that a better understanding of both the progenitor cells that are responsible for the formation and maintenance of the articular cartilage and the signals required to maintain the proliferation, viability and/or differentiated phenotype of superficial zone chondrocytes will eventually lead to the development of therapeutic reagents to restore this tissue during osteoarthritis. PUBLIC HEALTH RELEVANCE: Osteoarthritis is a degenerative disease of the articular cartilage. We will investigate in vivo if superficial cells of the articular cartilage comprise a progenitor cell population for the articular cartilage in the adult and will determine whether the Notch and/or Wnt signaling pathways play a role in either the maintenance and/or expansion of these cells. Identification of the progenitor cells and signaling pathways that are responsible for maintenance of the superficial articular cartilage cell layer may provide a therapeutic insight into restoring this tissue during osteoarthritis.